PROJECT SUMMARY/ABSTRACT In the United States, lung cancer causes more deaths than colorectal, breast, and prostate cancers combined. The National Lung Screening Trial (NLST) showed a 20% reduction in lung cancer mortality among current and former heavy smokers who were screened with low dose computed tomography (LDCT) versus chest ra- diography. Although false positive results were common, affecting one quarter of trial participants, and some professional organizations raised concerns over the fact that NLST results may not be generalizable to the U.S. population, in December 2013 the U.S. Preventive Services Task Force began recommending annual lung cancer screening with LDCT in adults aged 55 to 80 years who are current or former (quit within the past 15 years) smokers and have a 30 pack-year smoking history. There is limited evidence on the effectiveness of lung cancer screening (LCS) in patients with comorbid conditions or functional limitations as NLST participants were required to be healthy enough to undergo surgical resection, which resulted in the enrollment of fairly healthy participants. While patients with significant smoking exposure have higher risk of developing lung can- cer, they also tend to have more underlying disease, may experience higher competing mortality risks, and may be ineligible for standard of care treatments used for early-stage lung cancer; hence, there is a need to evaluate the effectiveness of LCS in patients with preexisting medical comorbidities and functional limitations. Our long-term goal is to determine if risk-based LCS, that incorporates preexisting patient comorbid conditions and measures of frailty, improves our ability to determine which subgroups of patients are most likely to benefit from LCS while also identifying subgroups in whom LCS likely does more harm than good. The objective of this application is to evaluate the extent to which patient comorbidities and functional status impact LCS outcomes in a population-based setting. We hypothesize that incorporating information on patient?s baseline lung cancer risk score, comorbid conditions, and functional status will improve the benefit to harm ratio for certain sub- groups of the population. We plan to accomplish this objective by pursuing the following three specific aims: (1) determine the association of baseline lung cancer risk score on LCS; (2) assess the impact of comorbid condi- tions on LCS; and (3) evaluate the effect of functional status on LCS. This study utilizes existing infrastructure from a population-based registry to explore an emerging clinically relevant cancer screening area for which lim- ited data exist. The proposed research is significant because it will provide real-world data on LCS in patients by baseline risk, comorbid conditions, and functional status to generate evidence-based medicine of lung can- cer screening in clinical practice.